Chronic kidney disease (CKD) is a growing pandemic associated with very high mortality rates due to cardiovascular disease. Standard cardiovascular risk factors do not account for the increased risk associated with CKD. Novel risk factors discovered in the study of CKD: phosphorus, vascular calcification, and fibroblast growth factor 23 (FGF23) are all incorporated in the new chronic kidney disease - mineral bone disorder (CKD-MBD) syndrome. The cause of the CKD-MBD was unknown until recent progress stemming from the previous funding period of this application, and there was no therapy addressing cardiovascular risk. In its inception, the CKD-MBD is characterized by a developing osteodystrophy, stimulation of vascular calcification and stimulation of osteocytic protein levels in the circulation. We have found that the CKD-MBD is caused by increased renal production of circulating Wnt inhibitors and changes in c-klotho function. In a model of early CKD in the background of atherosclerosis and diabetes stimulated vascular calcification, we demonstrated increased production of Dkk-1 in the remnant kidney and increased circulating Dkk-1, sclerostin and c-klotho. Neutralization of Dkk-1 by a monoclonal antibody stimulated bone formation rates, corrected the osteodystrophy, prevented CKD stimulated vascular calcification (VC), and increased the expression of membrane c-klotho in the aorta and kidney. In addition, the osteoblastic transcription factor, RUNX2 was inhibited in the aorta, and vascular smooth muscle contractile protein expression was increased. Increased plasma c-klotho and FGF23 levels were not affected by Dkk-1 neutralization, but FGF23 levels were reduced to normal by phosphate binder therapy. Phosphate binder therapy had no effect on vascular calcification, but combined with the Dkk-1 antibody the CKD-MBD as characterized in the CKD-2 mice was completely treated. The aims of the current application ask whether the treatment of the CKD-MBD in early CKD, improves cardiovascular outcomes. In aim one, the effects of neutralization of the Wnt inhibitor, Dkk-1, on vascular stiffness will be studied using our vascular calcification model and murine model of Alport's syndrome. In aim two, the effects of neutralization of the Wnt inhibitor, Dkk-1, on survival and cardiac function in CKD will be studied. In aim three, the question of whether, early control of phosphate homeostasis and FGF23 add to the effects of treating the CKD-MBD with neutralization of the Wnt inhibitor, Dkk-1, will be analyzed. The successful completion of the proposed studies will provide preclinical proof of concept that treatment and prevention of the CKD-MBD improves cardiovascular outcomes in CKD, a major innovation, paving the pathway to clinical trials.